Large ring gold-sulfur-phosphine chelates

ABSTRACT

1. A COMPOUND OF THE FORMULA: AU-S-(CH2)N-P(-R1)-R2 . AU-S-(CH2)N-P(-R1)-R2 IN WHICH: R1 AND R2 ARE EACH LOWER ALKYL OF FROM ONE TO THREE CARBON ATOMS, PHENYL PHENYL SUBSTITUTED WITH A MEMBER SELECTED FROM THE GROUP OF ALKYL, ALKOXY OR HALOGEN, EACH ALKYL OR ALKOXY HAVING FROM ONE TO THREE CARBON ATOMS, OR, WHEN LOWER ALKYL, ARE JOINED TOGETHER WITH THE PHOSPHORUS ATOM TO WHICH THEY ARE ATTACHED TO FORM A RING; AND N IS TWO OR FOUR.

United States Patent 3,842,108 LARGE RING GOLD-SULFUR-PHOSPHINE CHELATES Blaine M. Sutton, Hatboro, and Joseph Weinstock, Phoenixville, Pa. assignors to Smithkline Corporation, Philadelphia, Pa. N0 Drawing. Filed Aug. 1, 1973, Ser. No. 384,665 Int. Cl. C07f 1/12 US. Cl. 260430 3 Claims ABSTRACT OF THE DISCLOSURE Large ring gold-sulfur-phosphine chelates having antiarthritic activity are prepared by reaction of an appropriate thioalkylphosphine with a phosphine gold halide in the presence of alkali.

This invention relates to novel large ring gold-sulfurphosphine chelates which have useful pharmacological activity. More specifically, the compounds of this invention have anti-arthritic activity as measured by their ability to inhibit adjuvant-induced polyarthritis in rats.

The compounds of this invention are represented by the following structural formula:

in which:

R and R are each lower alkyl of from one to three carbon atoms, phenyl, phenyl substituted with a member selected from the group of alkyl, alkoxy or halogen, each alkyl or alkoxy having from one to three carbon atoms, or, when lower alkyl, are joined together with the phosphorus atoms to which they are attached to form a ring; and

n is two to four.

Preferred compounds of this invention are represented by Formula I where R and R are lower alkyl of from one to three carbon atoms and n is two.

The compounds of this invention are prepared by reaction of an appropriate substituted thioalkylphosphine with a phosphine gold halide, for example chloro(trieth ylphosphine)gold, in the presence of alkali such as sodium or potassium hydroxide in a solvent such as aqueous alcohol at about 25 for approximately one hour.

The phosphine gold halides employed as starting materials are prepared by reaction of a cold (10 to --5) solution of gold(I) chloride, prepared by mixing thiodiglycol and gold acid chloride trihydrate in aqueous alcohol, with an appropriate phosphine such as triethylphosphine. Other procedures which may be applied to the preparation of these intermediates are found in J. Chem. Soc. 1828 (1937) and 1235 (1940) and Australian J. Chem. 19:547 (1966).

The substituted thioalkylphosphines are prepared as described in French Patent 1,401,930 [C.A. 63:11615h (1965)] from reaction of a phosphine, for example diethylphosphine, with an alkylene sulfide such as ethylene sulfide and sodium in liquid ammonia or phenyl lithium. Alternatively, the substituted thioalkyl phosphines are prepared by irradiation of a mixture of the corresponding substituted alkenyl phosphine, for example allyldiethylphosphine, and thiolacetic acid followed by basic hydrolysis of the intermediate thioacetate to the desired thiol. The substituted alkenyl phosphines are either known or are prepared from reaction of an alkenyl magnesium halide with a substituted chlorophosphine such as diethylchlorophosphine [J. Chem. Soc. 1446 (1947), 411 1951)]. Other procedures which may be used to prepare the alkenyl phosphines are found in German Patent 3,842,108 Patented Oct. 15, 1974 2,057,771 [C.A. :49333y (1971)] and Chem. Ber. 92:2088 (1959).

The anti-arthritic activity of the compounds of this invention is measured by their ability to inhibit adjuvantinduced polyarthritis in rats. The compounds of Formula I produce marked inhibition of the development of adjuvant arthritis in rats at daily oral doses as low as about 18 mg. per kilogram of body weight. Of particular im portance is the attainment of significant serum levels of gold following oral administration of these doses.

Adjuvant arthritis in rats is produced by a single injection of 0.75 mg. of Mycobacterium butyricum' suspended in white parafiin (N.F.) into a-hindpaw (left footpad). The injected leg becomes inflamed and reaches a. maximum volume in three to five days (primary lesion). The animals exhibit a decrease in 'body weight gain during this intial period. Adjuvant arthritis (secondary phase) occurs after a delay of approximately ten days and is characterized by inflammation of the non-injected sites (right hind leg), decrease in body weight gain and further increases in the volume of the injected hind leg. The compounds of Formula I administered in the doses described above beginning on the day of adjuvant injection and continuing for 17 days thereafter, exclusive of days 4, 5, 11 and 12, protect the animals against development of both primary and secondary lesions of adjuvant arthritis.

The compounds of this invention are administered in conventional dosage unit forms by incorporating an amount sufiicient to produce anti-arthritic activity, without toxic effects, with a nontoxic pharmaceutical carrier according to accepted procedures. Preferably the dosage units will contain a gold-sulfur-phosphine chelate of Formula I in an amount of from about 0.5 mg. to about 25 mg., preferably 0.5 mg. to 10 mg. calculated on gold content, per unit.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent can include any time delay material well known to the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid carrier is used the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 g. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension.

The method of producing anti-arthritic activity in accordance with this invention comprises administering internally to an animal organism a gold-sulfur-phosphiue chclate of Formula I, usually combined with a pharmaceutical carrier, in an amount sufiicient to produce antiarthritic activity without limiting side effects. The active medicament will be administered in a dosage unit, as described above, orally or parenterally, the oral route being preferred. Advantageously equal doses will be administered one or two times daily with the daily dosage regimen being from about 0.5 mg. to about 25 mg., preferably 0.5 mg. to about 10 mg., calculated on gold content. When the method described above is carried out, anti-arthritic activity is produced with a minimum of side effects.

The pharmaceutical preparations are made following the conventional techniques of the pharmaceutical chemist involving mixing, granulating and compressing when necessary, or variously mixing and dissolving the ingredients as appropriate to the desired end product.

The following examples illustrate the preparation of compounds of this invention and their incorporation into pharmaceutical compositions, and as such are not to be considered as limiting the invention set forth in the claims appended hereto. Temperatures are in degrees Centigrade unless otherwise stated.

EXAMPLE 1 Di-,u- (diethylphosphinoethylthio di gold A solution of 10.0 g. (0.08 mol) of thiodiglycol in 25 ml. of ethanol was mixed with a solution of 15.76 g. (0.04 mol.) of gold acid chloride trihydrate in 75 ml. of distilled water. When the bright orange-yellow solution was almost colorless, it was cooled to below and an equally cold solution of 5.0 g. (0.0425 mol.) of triethylphosphine in 25 ml. of ethanol was added dropwise to the stirred solution. After addition, the cooled mixture was stirred for 30 minutes. The solid that separates was removed by filtration and the filtrate was concentrated to about 30 ml. to yield a second crystal crop. The combined solid was washed with aqueous ethanol (2:1) and recrystallized from ethanol by addition of water to the cloud point to give chloro(triethylphosphine)gold as white needles, m.p. 85-86".

To a solution of 8.5 g. (0.37 mol.) of sodium in 500 ml. of liquid ammonia under nitrogen is added 37 g. (0.41 mol.) of diethylphosphine. After minutes a solution of 22 g. (0.38 mol.) of ethylene sulfide in m1. of ether is added dropwise. The ammonia is then removed and the residue is treated with 250 ml. of ether and 250 ml. of aqueous ammonium chloride. The ether layer is dried, filtered through Linde molecular sieves, evaporated and the residue is distilled to give diethyl(2-thioethyl)phosphine, b.p. 4344 (0.001 mm.).

To a solution of 8.50 g. (0.0565 mol.) of diethyl(2- thioethyl)phosphine in 40 ml of ethanol was added a solution of 2.26 g. (0.0565 mol.) of sodium hydroxide in 40 ml. of 1:1 water-ethanol followed by a solution of 19.8 g. (0.056 mol.) of chloro(triethylphosphine)gold in 60 ml. of 2:1 chloroform-ethanol. After stirring for one hour, the solution was filtered and evaporated to dryness and the residue was extracted with about 200 ml. of chloroform. The extract was dried and concentrated in vacuo to give a yellow oil which crystallized upon cooling. The solid was washed with ether and recrystallized from methanol to give the title compound, m.p. 136138.

EXAMPLE 2 Di-;/.- (diethylphosphinobutylthio) di gold To a solution of a Grignard reagent prepared from 67.5 g. (0.50 mol.) of 4-bromo-1-butene and 14.6 g. (0.60 g.-atom) of magnesium turnings in 400 ml. of dry ether is slowly added under nitrogen 21 solution of 62.5 g. (0.05 mol.) of diethylchlorophosphine in 500 m1. of dry benzene. The reaction mixture is refluxed for two hours, then cooled under nitrogen and hydrolyzed with saturated aqueous ammonium chloride. The layers are separated and the organic layer is dried and distilled to give diethyl- (4-butenyl)phosphine as a colorless liquid.

A solution of 14.5 g. (0.10 mol.) of diethyl(4-butenyl) phosphine and 8.4 g. (0.11 mol.) of thiolacetic acid in 50 ml. of carbon tetrachloride is irradiated in a Pyrex flask with a mercury vapor lamp for 1.5 to 2 hours under a nitrogen atmosphere. The reaction mixture is distilled to give diethyl(4-acetylthiobutyl)phosphine as a liquid.

A solution of 1.0 g. (0.025 mol.) of sodium hydroxide in 20 ml. of 50% aqueous ethanol and a solution of 5.5 g. (0.025 mol.) of diethyl(4-acetylthiobutyl)phosphine and 8.75 g. (0.025 mol.) of chloro(triethylphosphine)gold in ml. of chloroform-ethanol (2:1) are stirred under nitrogen for one hour at 25 The reaction mixture is evaporated to dryness, chloroform is added to the residue and the chloroform solution is washed with water and concentrated to give the title compound.

4 EXAMPLE 3 Di-,u- (diphenylphosphinopropylthio digold The title compound is prepared by irradiation of 22.6 g. (0.10 mol.) of allyldiphenylphosphine and 8.4 g. (0.11 mol.) of thiolacetic acid followed by basic hydrolysis of the intermediate thioacetate and reaction of the thiol with chloro(triethylphosphine) gold as described in the procedure of Example 2.

EXAMPLE 4 Dimethyl(2-thioethyl)phosphine is prepared from dimethylphosphine and ethylene sulfide by the procedure of Example 1. When an equivalent amount of dimethyl(2- thioethyl)phosphine is substituted in the procedure of Example 1 for diethyl(Z-thioethyl)phosphine, di-;u.-(dirnethylphosphinoethylthio)digold is obtained.

Similarly, methylethyl(2 thioethyl)phosphine is obtained from methylethylphosphine (U.S. 3,075,017) and ethylene sulfide. Substitution of an equivalent amount of methylethyl(2-thioethyl)phosphine in the procedure of Example 1 for diethyl(Z-thioethyl)phosphine gives di-;1.- (methylethylphosphinoethylthio di gold.

In the same manner, diisopropyl(2-thioethyl)phosphine is obtained from ethylene sulfide and diisopropylphosphine [J. Organom'etal. Chem. 13:283 (1968)] and is substituted in the procedure of Example 1 for diethyl(Z-thioethyl) phosphine to give di-,u.(diisopropylphosphinoethylthio)digold.

EXAMPLE 5 To a solution of 37.2 g. (0.21 mol.) of diphenyl phosphine in ml. of ether is added dropwise 200 ml. of 1M phenyl lithium solution, followed by a solution of 12 g. (0.20 mol.) of ethylene sulfide in 100 ml. of ether with cooling. The reaction mixture is stirred for three hours at 25 then 100 ml. of methanol and 50 ml. of saturated aqueous ammonium chloride solution are added. The ether layer is separated, washed, dried and distilled to give diphenyl(2-thioethyl)phosphine, b.p. 152-153 (0.05 mm.).

When an equivalent amount of diphenyl(Z-thioethyl) phosphine is substituted in the procedure of Example 1 for diethyl(2-thioethyl)phosphine, di- -(diphenylphosphinoethylthio)digold is obtained.

Reaction of ethylphenylphosphine (U.S. 3,019,248) and ethylene sulfide as described in Example 1 or above gives ethylphenyl(2-thioethyl)phosphine. Substitution of an equivalent amount of ethylphenyl(2-thioethyl)phosphine 1n the procedure of Example 1 for diethyl(Z-thioethyl) phfiisphine gives di-n-(ethylphenylphosphinoethylthio)digo EXAMPLE 6 (2-Thioethy1)phospholane is prepared from phospholane (U.S. 3,086,056) and ethylene sulfide by the procedure of Example 1 or Example 5. When an equivalent amount of (2-thioethyl)phospholane is substituted in the procedure of Example 1 for diethyl(Z-thioethyl)phosphine, di-,u.-(phospholanoethylthio)digold is obtained.

In like manner, (2-thioethyl)phosphane is prepared from phosphane (US. 3,086,056) and ethylene sulfide. Substitution of an equivalent amount of (2-thioethyl) phosphane in the procedure of Example 1 for diethyl(2- thiloiethyhphosphine gives di- -(phosphanoethylthio)digo EXAMPLE 7 When o-tolylphenylphosphine, p-tolylphenylphosphine, o-methoxyphenylphenylphosphine and o-chlorophenylphenylphosphine [J. Chem. Soc. 1327 (1963)] are allowed to react with ethylene sulfide by the procedure described in Example 1 or Example 5 the following 2-thioethyl phosphines are obtained:

o-tolylphenyl(2-thioethyl)phosphine p-tolylphenyl(2-thioethyl)phosphine o-methoxyphenylphenyl Z-thioethyl phosphine o-chlorophenylphenyl(2-thioethyl)phosphine.

Substitution of an equivalent amount of a 2-thioethyl phosphine listed above in the procedure of Example 1 for diethyl(2-thioethyl)phosphine gives the following goldsulfur-phosphine complexes:

di- (o-tolylphenylphosphinoethylthio) digold di- (p-tolylphenylphosphinoethylthio digold di-no-methoxyphenylphenylphosphinoethylthio di gold dio-chlorophenylphenylphosphinoethylthio digold.

EXAMPLE 8 Ingredients: Mg./Tablet Di- (diethylphosphinoethylthio) digold 5 Calcium sulfate, dihydrate 150 Sucrose 25 Starch 15 Talc 5 Stearic acid 3 6 in which:

R and R are each lower alkyl of from one to three carbon atoms, phenyl, phenyl substituted with a member selected from the group of alkyl, alkoxy or halogen, each alkyl or alkoxy having from one to three carbon atoms, or, when lower alkyl, are joined together with the phosphorus atom to which they are attached to form a ring; and

n is two to four.

2. A compound as claimed in claim 1 where R and R are lower alkyl of from one to three carbon atoms and n is two.

3. A compound as claimed in claim 2 where R and R are ethyl, said compound being dir-(diethylphosphinoethylthio)digold.

References Cited UNITED STATES PATENTS 3,635,945 1/1972 Nemeth et al 260430 X 3,676,554 7/1972 McGusty et a1. 260430 X 3,718,679 2/1973 McGusty et a1. 260430 3,718,680 2/1973 McGusty et a1. 260430 OTHER REFERENCES Mann et al., J. Chem. Soc., pp. 1235-1239 (1940).

J. Chem. Soc., 1828-1836 (1937).

Coates et al., Aus. J. Chem., vol. 19, 539-545 (1966). 'Kowala et al., Aus. J. Chem., vol. 19, 547-554 (1966). Aus. J. Chem., vol. 19, pp. 555-559 (1966).

Chiswell et al., J. Chem. Soc. (A), pp. 901-902 (1966).

H. M. S. SNEED, Primary Examiner US. Cl. X.R. 424290 

1. A COMPOUND OF THE FORMULA: AU-S-(CH2)N-P(-R1)-R2 . AU-S-(CH2)N-P(-R1)-R2 IN WHICH: R1 AND R2 ARE EACH LOWER ALKYL OF FROM ONE TO THREE CARBON ATOMS, PHENYL PHENYL SUBSTITUTED WITH A MEMBER SELECTED FROM THE GROUP OF ALKYL, ALKOXY OR HALOGEN, EACH ALKYL OR ALKOXY HAVING FROM ONE TO THREE CARBON ATOMS, OR, WHEN LOWER ALKYL, ARE JOINED TOGETHER WITH THE PHOSPHORUS ATOM TO WHICH THEY ARE ATTACHED TO FORM A RING; AND N IS TWO OR FOUR. 